Analysis of effects of acute hypovolemia on arterial stiffness in rabbits monitored with cardio-ankle vascular index.

Although elasticity of the conduit arteries is known to be contribute effective peripheral circulation via Windkessel effects, the relationship between changes in intra-aortic blood volume and conduit artery elasticity remains unknown. Here we assessed the effects of change in intra-aortic blood volume induced by blood removal and subsequent blood transfusion on arterial stiffness and the involvement of autonomic nervous activity using our established rabbit model in the presence or absence of the ganglion blocker hexamethonium (100 mg/kg). Blood removal at a rate of 1 mL/min gradually decreased the blood pressure and blood flow of the common carotid artery but increased a stiffness indicator the cardio-ankle vascular index, which was equally observed in the presence of hexamethonium. These results suggest that arterial stiffness acutely responds to changes in intra-aortic blood volume independent of autonomic nervous system modification.

The Effect of Nitroglycerin on Arterial Stiffness of the Aorta and the Femoral-Tibial Arteries.

AIM: The effect of nitroglycerin on proper arterial stiffness of the arterial tree has not been fully clarified. The cardio-ankle vascular index (CAVI), which is an application of the stiffness parameter ß theory on the arterial tree from the origin of the aorta to the ankle, was developed recently. Furthermore, the stiffness of the aorta (heart-thigh ß (htBeta)) and of the femoral-tibial arteries (thigh to ankle ß (taBeta)) could be monitored by applying the same theory. The effects of nitroglycerin on CAVI, htBeta, and taBeta were studied comparing the values of healthy people and those of arteriosclerotic patients. METHODS: The subjects were healthy people (CAVI ＜7.5, n=25) and arteriosclerotic patients (CAVI ＞9, n=25). Nitroglycerin (0.3 mg) was administrated sublingually, and various arterial stiffness indices were measured at one-minute intervals for a period of 20 minutes using Vasera VS-1500 (Fukuda Denshi, Tokyo). RESULTS: After the administration of nitroglycerin in healthy people, CAVI decreased significantly after 5 min. [from 6.76(6.32-7.27) to 5.50(4.70-6.21), P＜0.05], and recovered after 15 min. htBeta [from 5.10(4.76-5.76) to 3.96(3.35-4.79), P＜0.05], and taBeta [from 14.41(10.80-16.33) to 10.72 (9.19-13.01), P＜0.05] also decreased significantly. In arteriosclerotic patients, CAVI decreased after 5 min. [from 10.47(9.67-11.29) to 9.71(8.74-10.57), P＜0.05] and recovered after 15 min. htBeta did not significantly change [from 12.00(11.46-13.21) to 11.81(10.14-13.83), ns], but taBeta decreased significantly [from 18.55(12.93-23.42) to 12.37(9.68-16.99), P＜0.05]. CONCLUSION: These results indicate that a nitroglycerin-induced decrease of arterial stiffness is more prominent in muscular arteries than in elastic arteries, and this effect was preserved much more prominently in arteriosclerotic patients than in healthy people.

Soluble form of LR11 is highly increased in the vitreous fluids of patients with idiopathic epiretinal membrane.

PURPOSE: LR11 (also called SorLA or SORL1) is a migration regulator of adherent cells with the immature proliferative phenotype. The present study investigated the clinical and pathological involvement of the soluble form of LR11 (sLR11) in the idiopathic epiretinal membrane (iERM). METHODS: The subjects were 51 patients with iERM (24 cellophane macular reflex (CMR) and 27 preretinal macular fibrosis (PMF)) and 45 patients with macular holes as age and sex-matched controls. Vitreous sLR11 and transforming growth factor (TGF)ß2 levels were measured by ELISA. RESULTS: The sLR11 levels in the vitreous fluids of patients with iERM (20.2 ± 8.1 ng/mL) were significantly higher than those in controls (11.4 ± 4.7 ng/mL). Among the patients with iERM, the vitreous sLR11 levels were significantly higher in PMF (23.6 ± 8.2 ng/mL), than those in CMR (16.5 ± 5.9 ng/mL). Multivariate regression analysis of the studied factors showed that sLR11 was a unique factor independently contributing to the discrimination of the iERM patients against the control subjects (odds ratio [OR] 1.35 per 1-ng/mL increase, 95% CI 1.09-1.67; P = 0.004). ROC analysis showed that the sensitivity and the specificity of sLR11, but not of other studied factors, categorized into the rank of moderate accuracy. Finally, there was a positive correlation (R = 0.588; P = 0.003) between the vitreous levels of sLR11 and TGFß2 using the available samples. CONCLUSIONS: sLR11 levels in vitreous fluids were specifically increased in patients with iERM, suggesting the involvement in the pathology of proliferative and migrating cells for the development of iERM.

Arteriosclerotic Changes after Intravitreal Injections of Anti-Vascular Endothelial Growth Factor Drugs in Patients with Exudative Age-Related Macular Degeneration.

PURPOSE: The aim of this study was to determine whether multiple intravitreal injections of anti-vascular endothelial growth factor (VEGF) drugs for age-related macular degeneration (AMD) exacerbate systemic arteriosclerosis, using the cardio-ankle vascular index (CAVI) and intima-media thickness (IMT). METHODS: We analyzed the data of 45 AMD patients who received intravitreal injections of anti-VEGF drugs (ranibizumab and/or aflibercept) and underwent systemic evaluations at baseline and after treatment. Reevaluation was conducted at ≥12 months from the initial treatment. RESULTS: The total number of intravitreal injections of overall anti-VEGF drugs was significantly correlated with x0394;serum cystatin C. The cumulative number of aflibercept injections was identified as an independent protective factor for x0394;CAVI. An increase in the cumulative number of intravitreal injections of overall anti-VEGF drugs was identified as a protective factor for x0394;mean IMT. CONCLUSION: Repeated intravitreal injections of an anti-VEGF drug for AMD may lead to morphological and functional changes in large arteries.

The Role of Monitoring Arterial Stiffness with Cardio-Ankle Vascular Index in the Control of Lifestyle-Related Diseases.

Arteriosclerosis is a major contributor to cardiovascular diseases. One of the difficulties in controlling those diseases is the lack of a suitable indicator of arteriosclerosis or arterial injury in routine clinical practice. Arterial stiffness was supposed to be one of the monitoring indexes of arteriosclerosis. Cardio-ankle vascular index (CAVI) is reflecting the stiffness of the arterial tree from the origin of the aorta to the ankle, and one of the features of CAVI is independency from blood pressure at a measuring time. When doxazosin, an α1-adrenergic blocker, was administered, CAVI decreased, indicating that arterial stiffness is composed of both organic stiffness and functional stiffness, which reflects the contraction of arterial smooth muscle. CAVI shows a high value with aging and in many arteriosclerotic diseases, and is also high in persons possessing main coronary risk factors such as diabetes mellitus, metabolic syndrome, hypertension and smoking. Furthermore, when the most of those risk factors were controlled by proper methods, CAVI improved. Furthermore, the co-relationship between CAVI and heart function was demonstrated during treatment of heart failure. This paper reviews the principle and rationale of CAVI, and discusses the meaning of monitoring CAVI in following up so-called lifestyle-related diseases and cardiac dysfunction in routine clinical practice.

Two cases of acute abdomen after an intravitreal injection of bevacizumab.

We report on a patient with ischemic colitis and another with paralytic ileus, both of whom experienced an acute abdomen after intravitreal injection of bevacizumab (IVB). Case 1 was a 78-year-old woman. Her medical history included surgery for colon carcinoma 10 years earlier. The patient developed acute severe abdominal pain and nausea the day after IVB for retinal vein occlusion with macular edema, and massive lower gastrointestinal bleeding occurred. Ischemic colitis was diagnosed. Case 2 was a 64-year-old man who presented with neovascular glaucoma with proliferative diabetic retinopathy. We performed vitreous surgery on the 9th day after IVB, and we reperformed IVB at the end of the vitreous surgery. On the first postoperative day, severe abdominal distension, vomiting and abdominal pain were observed, and paralytic ileus was diagnosed. It is possible that gastrointestinal disorders are induced after IVB, depending on the patient's background, including for example severe diabetes or a history of surgery for gastrointestinal cancer. Thus, ophthalmologists should apply alternative therapies instead of IVB to patients with severe diabetes mellitus or a history of gastrointestinal cancer.

Evaluation of plasma vascular endothelial growth factor levels after intravitreal injection of ranibizumab and aflibercept for exudative age-related macular degeneration.

BACKGROUND: To evaluate the plasma vascular endothelial growth factor (VEGF) levels after one intravitreal injection of aflibercept or ranibizumab in patients with exudative age-related macular degeneration (AMD). METHODS: Twenty-four Japanese with exudative AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation were included. Fourteen patients received an intravitreal injection of aflibercept, and ten patients received an intravitreal injection of ranibizumab. Plasma VEGF levels were evaluated within 7 days before the intravitreal injections and 1 day, 1 week, and 1 month after the intravitreal injection. RESULTS: In the ranibizumab group, the mean plasma VEGF levels were 245.7 ± 233.4 pg/ml before the injection, 246.6 ± 304.8 pg/ml after 1 day, 217.8 ± 212.9 pg/ml after 1 week, and 260.0 ± 290.1 pg/ml after 1 month. The plasma VEGF levels did not decrease significantly in patients in the ranibizumab group at any time point. In the aflibercept group, the mean plasma VEGF levels were 280.0 ± 170.3 pg/ml before the intravitreal injection and 8.2 ± 12.9 pg/ml after 1 day, 9.1 ± 9.1 pg/ml after 1 week, and 41.9 ± 41.4 pg/ml after 1 month (p < 0.0001, vs before injection). CONCLUSION: Intravitreally injected aflibercept reduced plasma VEGF over at least 1 month. In contrast, intravitreal injection of ranibizumab did not cause a significant reduction in the plasma VEGF levels.

Pulse-Wave Analysis of Optic Nerve Head Circulation Is Significantly Correlated with Kidney Function in Patients with and without Chronic Kidney Disease.

Aim. To determine whether there is a significant correlation between the optic nerve head (ONH) circulation determined by laser speckle flowgraphy (LSFG) and kidney function. Materials. Seventy-one subjects were investigated. The estimated glomerular filtration rate (GFR) and serum creatinine, cystatin C, and urinary albumin excretion were measured. The ONH circulation was determined by an analysis of the pulse wave of LSFG, and this parameter was named blowout time (BOT). Chronic kidney disease (CKD) was defined to be present when the estimated GFR was <60 mL/min per 1.73 m(2). Pearson's correlation coefficients were used to determine the relationship between the BOT and the kidney function. We also examined whether there were significant differences in all parameters in patients with and without CKD. Results. BOT was significantly correlated with the level of creatinine (r = -0.24, P = 0.04), the estimated GFR (r = 0.42, P = 0.0003), cystatin C (r = -0.29, P = 0.01), and urinary albumin excretion (r = -0.29, P = 0.01). The BOT level in subjects with CKD was significantly lower than that in subjects without CKD (P = 0.002). Conclusion. BOT in ONH by LSFG can detect the organ damage such as kidney dysfunction, CKD.

[Nocturnal dipping of heart rate in patients with proliferative diabetic retinopathy and iris and/or angle neovascularization].

PURPOSE: To evaluate the relationship between nocturnal dipping in heart rates and iris and/or angle neovascularization (NV) in patients with proliferative diabetic retinopathy(PDR). SUBJECTS AND METHOD: One hundred fifty-one patients with PDR who underwent surgery were divided into groups based on either the presence or absence of iris and/or angle NV (NV group, 37; non-NV group, 114 patients). Pulse oximetry was conducted overnight and the heart rates were measured both before and during sleep; the resting and nocturnal heart rates and the resting-nocturnal heart rate dip ratio were calculated. RESULTS: The resting and nocturnal heart rates did not differ significantly between the two groups. The resting-nocturnal heart rate dip ratio was significantly lower in the NV group than in the non-NV group (p = 0.006). In the NV group, the frequency of insulin therapy (p = 0.003) and a history of coronary artery disease were significantly (p = 0.033) higher than in the non-NV group. Pearson's correlation analysis showed that only the NV group was significantly negatively correlated with the resting-nocturnal heart rate dip ratio (r = -0.18, t value = -2.2, p = 0.028). CONCLUSION: In patients with PDR, the non-occurrent of nocturnal dip in heart rate may be a related factor for iris and/or angle neovascularization.

[Prevalence of sleep-disordered breathing in patients with retinal vein occlusion].

PURPOSE: To investigate the prevalence of sleep-disordered breathing (SDB) in retinal vein occlusion (RVO) patients. SUBJECT AND METHOD: Forty RVO patients who had undergone either vitreous surgery or anti-coagulation therapy were included in this study. Pulse oximetry was conducted during the night and 4% oxygen desaturation index (4% ODI times/hour) and mean SpO2 (%) were calculated. If 4% ODI > or = 5, SDB was diagnosed. The results were compared between branch retinal vein occlusion (BRVO), and central retinal vein occlusion (CRVO). In addition, simple linear regression analyses were conducted to investigate whether 4% ODI related to systemic factors for RVO patients, i.e., incidences of hypertension and diabetes and body mass index(BMI kg/m2). RESULTS: Forty two percent of the men, 33% of the women and 37% of all the RVO patients were diagnosed as having SDB. The prevalence of SDB and 4% ODI, and the mean SpO2 were not significantly different between the BRVO and CRVO cases. The incidences of diabetes tended to correlate to the 4% ODI, however, neither proved significant. The BMI had a statistic correlation with the 4% ODI. CONCLUSION: The results of our study suggested that RVO cases have a high frequency of SDB. We believe that at the time of ophthalmic medical examinations or during the treatment of RVO, ophthalmologists should be aware of the possibility of SDB.

Cardio-ankle vascular index (CAVI) as a novel indicator of arterial stiffness: theory, evidence and perspectives.

The cardio-ankle vascular index (CAVI) is a new index of the overall stiffness of the artery from the origin of the aorta to the ankle. The most conspicuous feature of CAVI is its independence of blood pressure at the time of measurement.CAVI increases with age and in many arteriosclerotic diseases, such as coronary artery disease, carotid arteriosclerosis, chronic kidney disease and cerebrovascular disease, and is related to many coronary risk factors, such as hypertension, diabetes mellitus, dyslipidemia and smoking. Furthermore, CAVI decreases by controlling diabetes mellitus and hypertension, and also by abstaining from smoking. This suggests that CAVI is a physiological surrogate marker of athero- or arteriosclerosis, and also might be an indicator of lifestyle modification.Recently, it has been reported that CAVI and several left ventricular functions are co-related, suggesting a connection between the heart muscle and vascular function.This review covers the principles of CAVI and our current knowledge about CAVI, focusing on its roles and future outlook.

Relationship between sleep-disordered breathing and iris and/or angle neovascularization in proliferative diabetic retinopathy cases.

PURPOSE: To investigate whether sleep-disordered breathing is a risk factor for iris and/or angle neovascularization in patients with proliferative diabetic retinopathy (PDR). DESIGN: Cross-sectional comparative case series. SUBJECTS AND METHODS: One hundred fifty-one consecutive patients with PDR who underwent surgery in our hospital were divided based on the presence of iris and/or angle neovascularization (NV group, 37 patients) or absence of NV (non-NV group, 114 patients). Pulse oximetry was conducted during the night and the mean SpO(2), 4% oxygen desaturation index (4% ODI times/hour), the lowest SpO(2)% during sleep (lowest SpO(2)), and the cumulative percentage of time at SpO(2) <90% in analysis times (CT90%) were calculated. When the 4% ODI exceeded 5 times/hour, sleep-disordered breathing was diagnosed. The results were compared between the 2 groups. Preoperative systemic parameters also were analyzed by logistic regression to clarify risk factors for the NV group. RESULTS: A mean total of 50% (62% of the NV group and 46% of the non-NV group) was diagnosed with sleep-disordered breathing. The mean SpO(2) and lowest SpO(2) did not differ significantly between the 2 groups; the 4% ODI (12.3 vs 6.6) and CT90% (3.8 vs 1.7) were significantly higher in the NV group (P=.02, for both comparisons). Logistic regression analysis identified insulin therapy (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.26∼7.20; P=.01); and 4% ODI (OR, 1.09; CI, 1.01∼1.16; P=.02) as risk factors for the NV group. CONCLUSIONS: In patients with PDR, nocturnal intermittent hypoxia/reoxygenation resulting from sleep-disordered breathing may be a risk factor for iris and/or angle neovascularization.

Changes in cardio-ankle vascular index in smoking cessation.

AIM: To investigate the effect of smoking and smoking cessation on cardio-ankle vascular index (CAVI). METHODS: The subjects were 82 smokers (77 men, 64+/-10 years) and 20 non-smokers (18 men, 61+/-7 years). CAVI was measured every 3 months and CAVI severity was classified into 3 levels. Decreased, unchanged, and increased CAVI severity levels were coded as "improvement," "no change," and "exacerbation," respectively. Smoking status was coded as "success" for complete abstinence, "partial success" for a reduced number of cigarettes, and "failure" for an unchanging number of cigarettes. RESULTS: Compared with non-smokers, smokers showed a higher CAVI (p<0.05) prior to smoking cessation. Post-cessation, CAVI improved from 9.4 to 8.6 (p<0.01) in "success" cases (n=22), and the significant pre-cessation difference from non-smokers (n=20, CAVI=8.8) disappeared. With regard to the change in CAVI severity of each smoking status, "improvement" occurred in 17%, 24%, and 68% of "failure" (n=35), "partial success" (n=25), and "success" (n=22) groups, respectively, and the "success" group was significantly higher than the other two groups. CONCLUSION: The study showed that CAVI was increased by smoking, and complete smoking cessation improved CAVI.

Association between cardio-ankle vascular index and serum cystatin C levels in patients with cardiovascular risk factor.

AIM: The aim of this study was to clarify the relationship between CAVI and serum cystatin C levels to understand the role of arterial stiffness in the presence of renal insufficiency. METHODS: We enrolled 206 consecutive patients with cardiovascular risk factors and/or coronary artery disease (CAD) in the study. Serum cystatin C, estimated glomerular filtration rate (eGFR), and plasma levels of von Willebrand factor (vWF) and plasminogen activator inhibitor (PAI-1) were measured. CAVI was determined as an index of arterial stiffness. RESULTS: For all patients, the mean serum cystatin C level was 0.81+/-0.21 mg/L and mean eGFR was 65.8+/-15.5 mL/min per 1.73 m(2). In univariate analysis, CAVI levels significantly correlated with cystatin C levels (r=0.414, p<0.001), eGFR (r=-0.315, p<0.01), PAI-1 (r=0.269, p<0.01), and vWF (r=0.207, p<0.01). Multiple regression analysis showed that age, cystatin C, PAI-1, and a history of CAD were independent variables of CAVI. Age-adjusted CAVI was highest in the presence of both CAD and renal impairment. CONCLUSION: CAVI was closely associated with cystatin C levels. These results suggest a significant role of arterial stiffness in renal insufficiency.

Relationship between diabetic retinopathy and sleep-disordered breathing.

PURPOSE: To clarify the relationships of sleep-disordered breathing (SDB) to nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). DESIGN: Cross sectional case-control study. METHODS: Forty-eight consecutive NPDR and 118 PDR cases that had undergone surgery in our hospital were included in this study. Pulse oximetry was conducted during the night and the sleeping 4% oxygen desaturation index (ODI) (number of oxygen desaturation events/hour exceeding 4%) and mean SpO(2)% were calculated. If 4% ODI > 5 times/hour, SDB was diagnosed. The results were evaluated and compared between the 2 groups. In addition, these results and preoperative patient background factors were analyzed using multiple regression analysis to identify correlations with the diagnosis of PDR. RESULTS: Twenty-nine percent of the NPDR and 48% of the PDR patients were diagnosed as having SDB. The incidence of SDB and the 4% ODI/hour value were significantly higher in the PDR than in the NPDR group (P = .003 and .03, respectively). Multiple regression analysis showed younger age and a higher 4% ODI value to be factors independently contributing to a diagnosis of PDR (age, standard regression coefficient = -0.34; t value = -4.44; P < .0001; 4% ODI, standard regression coefficient = 0.20; t value = 2.15; P = .03, correlation coefficient (R) = 0.43). CONCLUSION: Our results suggest that, in diabetic retinopathy patients with nocturnal desaturation, reoxygenation caused by SDB may relate to the development of PDR.

Relationship between metabolic syndrome and early stage coronary atherosclerosis.

AIM: Recent clinical studies using intra-vascular ultrasound have clarified that coronary artery plaque already exists in subjects with normal coronary artery which is diagnosed by coronary angiography; furthermore, culprit lesion on acute coronary syndrome often occurs in mild to moderate angiographical stenotic lesion. The aim of this study is to clarify relationship between metabolic syndrome and early stage coronary atherosclerosis using a 3-dimensional intra-vascular ultrasound. METHODS: 70 subjects with normal coronary artery diagnosed by coronary angiography were enrolled. Proxymal range of left anterior descending coronary artery was observed by intra-vascular ultrasound using autopullback methods. RESULTS: Subjects with metabolic syndrome had significantly high percent plaque volume (31 +/- 8% vs 21 +/- 8%, p < 0.0001) and frequently detected abnormal plaque quality such as eccentricity, calcification and lipid pool into plaque than those without metabolic syndrome. Multivariate analysis showed that serum adiponectin concentration was the most strongest variable for percent plaque volume (t value= - 3.0, p < 0.01). On the other hand, subjects with hypoadiponectinemia were detected high incidence of mild calcification into plaque. CONCLUSION: Metabolic syndrome needs to be detected and treated as early as possible. Furthermore, measurement of serum adiponectin concentration and appropriate treatment would prevent acute coronary syndrome.